Large-Scale Comparative Analyses of Tick Genomes Elucidate Their Genetic Diversity and Vector Capacities.

Among arthropod vectors, ticks transmit the most diverse human and animal pathogens, leading to an increasing number of new challenges worldwide. Here we sequenced and assembled high-quality genomes of six ixodid tick species and further resequenced 678 tick specimens to understand three key aspects of ticks: genetic diversity, population structure, and pathogen distribution. We explored the genetic basis common to ticks, including heme and hemoglobin digestion, iron metabolism, and reactive oxygen species, and unveiled for the first time that genetic structure and pathogen composition in different tick species are mainly shaped by ecological and geographic factors. We further identified species-specific determinants associated with different host ranges, life cycles, and distributions. The findings of this study are an invaluable resource for research and control of ticks and tick-borne diseases.

APC mutations disrupt ß-catenin destruction complex condensates organized by Axin phase separation.

The Wnt/ß-catenin pathway is critical to maintaining cell fate decisions. Recent study showed that liquid-liquid-phase separation (LLPS) of Axin organized the ß-catenin destruction complex condensates in a normal cellular state. Mutations inactivating the APC gene are found in approximately 80% of all human colorectal cancer (CRC). However, the molecular mechanism of the formation of ß-catenin destruction complex condensates organized by Axin phase separation and how APC mutations impact the condensates are still unclear. Here, we report that the ß-catenin destruction complex, which is constructed by Axin, was assembled condensates via a phase separation process in CRC cells. The key role of wild-type APC is to stabilize destruction complex condensates. Surprisingly, truncated APC did not affect the formation of condensates, and GSK 3ß and CK1α were unsuccessfully recruited, preventing ß-catenin phosphorylation and resulting in accumulation in the cytoplasm of CRCs. Besides, we propose that the phase separation ability of Axin participates in the nucleus translocation of ß-catenin and be incorporated and concentrated into transcriptional condensates, affecting the transcriptional activity of Wnt signaling pathway.

Potential drug targets for gastroesophageal reflux disease and Barrett's esophagus identified through Mendelian randomization analysis.

Gastroesophageal reflux disease (GERD) is a prevalent chronic ailment, and present therapeutic approaches are not always effective. This study aimed to find new drug targets for GERD and Barrett's esophagus (BE). We obtained genetic instruments for GERD, BE, and 2004 plasma proteins from recently published genome-wide association studies (GWAS), and Mendelian randomization (MR) was employed to explore potential drug targets. We further winnowed down MR-prioritized proteins through replication, reverse causality testing, colocalization analysis, phenotype scanning, and Phenome-wide MR. Furthermore, we constructed a protein-protein interaction network, unveiling potential associations among candidate proteins. Simultaneously, we acquired mRNA expression quantitative trait loci (eQTL) data from another GWAS encompassing four different tissues to identify additional drug targets. Meanwhile, we searched drug databases to evaluate these targets. Under Bonferroni correction (P < 4.8 × 10-5), we identified 11 plasma proteins significantly associated with GERD. Among these, 7 are protective proteins (MSP, GPX1, ERBB3, BT3A3, ANTR2, CCM2, and DECR2), while 4 are detrimental proteins (TMEM106B, DUSP13, C1-INH, and LINGO1). Ultimately, C1-INH and DECR2 successfully passed the screening process and exhibited similar directional causal effects on BE. Further analysis of eQTLs highlighted 4 potential drug targets, including EDEM3, PBX3, MEIS1-AS3, and NME7. The search of drug databases further supported our conclusions. Our study indicated that the plasma proteins C1-INH and DECR2, along with 4 genes (EDEM3, PBX3, MEIS1-AS3, and NME7), may represent potential drug targets for GERD and BE, warranting further investigation.

STING inhibitors target the cyclic dinucleotide binding pocket.

Cytosolic DNA activates cGAS (cytosolic DNA sensor cyclic AMP-GMP synthase)-STING (stimulator of interferon genes) signaling, which triggers interferon and inflammatory responses that help defend against microbial infection and cancer. However, aberrant cytosolic self-DNA in Aicardi-Goutière's syndrome and constituently active gain-of-function mutations in STING in STING-associated vasculopathy with onset in infancy (SAVI) patients lead to excessive type I interferons and proinflammatory cytokines, which cause difficult-to-treat and sometimes fatal autoimmune disease. Here, in silico docking identified a potent STING antagonist SN-011 that binds with higher affinity to the cyclic dinucleotide (CDN)-binding pocket of STING than endogenous 2'3'-cGAMP. SN-011 locks STING in an open inactive conformation, which inhibits interferon and inflammatory cytokine induction activated by 2'3'-cGAMP, herpes simplex virus type 1 infection, Trex1 deficiency, overexpression of cGAS-STING, or SAVI STING mutants. In Trex1-/- mice, SN-011 was well tolerated, strongly inhibited hallmarks of inflammation and autoimmunity disease, and prevented death. Thus, a specific STING inhibitor that binds to the STING CDN-binding pocket is a promising lead compound for STING-driven disease.

Correction: RNF111-facilitated neddylation potentiates cGAS-mediated antiviral innate immune response.

[This corrects the article DOI: 10.1371/journal.ppat.1009401.].

RNF111-facilitated neddylation potentiates cGAS-mediated antiviral innate immune response.

The cytosolic DNA sensor cyclic GMP-AMP (cGAMP) synthetase (cGAS) has emerged as a fundamental component fueling the anti-pathogen immunity. Because of its pivotal role in initiating innate immune response, the activity of cGAS must be tightly fine-tuned to maintain immune homeostasis in antiviral response. Here, we reported that neddylation modification was indispensable for appropriate cGAS-STING signaling activation. Blocking neddylation pathway using neddylation inhibitor MLN4924 substantially impaired the induction of type I interferon and proinflammatory cytokines, which was selectively dependent on Nedd8 E2 enzyme Ube2m. We further found that deficiency of the Nedd8 E3 ligase Rnf111 greatly attenuated DNA-triggered cGAS activation while not affecting cGAMP induced activation of STING, demonstrating that Rnf111 was the Nedd8 E3 ligase of cGAS. By performing mass spectrometry, we identified Lys231 and Lys421 as essential neddylation sites in human cGAS. Mechanistically, Rnf111 interacted with and polyneddylated cGAS, which in turn promoted its dimerization and enhanced the DNA-binding ability, leading to proper cGAS-STING pathway activation. In the same line, the Ube2m or Rnf111 deficiency mice exhibited severe defects in innate immune response and were susceptible to HSV-1 infection. Collectively, our study uncovered a vital role of the Ube2m-Rnf111 neddylation axis in promoting the activity of the cGAS-STING pathway and highlighted the importance of neddylation modification in antiviral defense.

Quantitative determination of rhamnolipid using HPLC-UV through carboxyl labeling.

Rhamnolipid, as a low-toxic, biodegradable and environmentally friendly biosurfactant, has broad application prospects in many industries. However, the quantitative determination of rhamnolipid is still a challenging task. Here, a new sensitive method for the quantitative analysis of rhamnolipid based on a simple derivatization reaction was developed. In this study, 3-[3'-(l-rhamnopyranosyloxy) decanoyloxy] decanoic acid (Rha-C10-C10) and 3-[3'-(2'-O-α-l-rhamnopyranosyloxy) decanoyloxy] decanoic acid (Rha-Rha-C10-C10) were utilized as the representative rhamnolipids. Liquid chromatography-mass spectrometry and high-performance liquid chromatography-ultra violet results showed that these two compounds were successfully labeled with 1 N1-(4-nitrophenyl)-1,2-ethylenediamine. There was an excellent linear relationship between rhamnolipid concentration and peak area of labeled rhamnolipid. The detection limits of the Rha-C10-C10 and Rha-Rha-C10-C10 were 0.018 mg/L (36 nmol/L) and 0.014 mg/L (22 nmol/L), respectively. The established amidation method was suitable for the accurate analysis of rhamnolipids in the biotechnological process. The method had good reproducibility with the relative standard deviation of 0.96% and 0.79%, respectively, and sufficient accuracy with a recovery of 96%-100%. This method was applied to quantitative analysis of 10 rhamnolipid homologs metabolized by Pseudomonas aeruginosa LJ-8. The single labeling method was used for the quantitative analysis of multiple components, which provided an effective method for the quality evaluation of other glycolipids with carboxyl groups.

The value of sociogenomics in understanding genetic evolution in contemporary human populations.

Burt's target article oddly misses the important intellectual contribution of sociogenomics to our understanding of genetic evolution in contemporary human populations. Although social scientists' immediate research agendas are often not evolutionary in nature, I call for a better appreciation of the role of sociogenomics in answering important evolutionary questions.

The dynamic changes in autophagy activity and its role in lung injury after deep hypothermic circulatory arrest.

Deep hypothermic circulatory arrest (DHCA) can cause acute lung injury (ALI), and its pathogenesis mimics ischaemia/reperfusion (I/R) injury. Autophagy is also involved in lung I/R injury. The present study aimed to elucidate whether DHCA induces natural autophagy activation and its role in DHCA-mediated lung injury. Here, rats were randomly assigned to the Sham or DHCA group. The sham group (n = 5) only received anaesthesia and air intubation. DHCA group rats underwent cardiopulmonary bypass (CPB) followed by the DHCA procedure. The rats were then sacrificed at 3, 6 and 24 h after the DHCA procedure (n = 5) to measure lung injury and autophagy activity. Chloroquine (CQ) was delivered to evaluate autophagic flux. DHCA caused lung injury, which was prominent 3-6 h after DHCA, as confirmed by histological examination and inflammatory cytokine quantification. Lung injury subsided at 24 h. Autophagy was suppressed 3 h but was exaggerated at 6 h. At both time points, autophagic flux appeared uninterrupted. To further assess the role of autophagy in DHCA-mediated lung injury, the autophagy inducer rapamycin and its inhibitor 3-methyladenine (3-MA) were applied, and lung injury was reassessed. When rapamycin was administered at an early time point, lung injury worsened, whereas administration of 3-MA at a late time point ameliorated lung injury, indicating that autophagy contributed to lung injury after DHCA. Our study presents a time course of lung injury following DHCA. Autophagy showed adaptive yet protective suppression 3 h after DHCA, as induction of autophagy caused worsening of lung tissue. In contrast, autophagy was exaggerated 6 h after DHCA, and autophagy inhibition attenuated DHCA-mediated lung injury.

The Arabidopsis AGC kinases NDR2/4/5 interact with MOB1A/1B and play important roles in pollen development and germination.

Pollen formation and pollen tube growth are essential for the delivery of male gametes into the female embryo sac for double fertilization. Little is known about the mechanisms that regulate the late developmental process of pollen formation and pollen germination. In this study, we characterized a group of Arabidopsis AGC kinase proteins, NDR2/4/5, involved in pollen development and pollen germination. The NDR2/4/5 genes are mainly expressed in pollen grains at the late developmental stages and in pollen tubes. They function redundantly in pollen formation and pollen germination. At the tricellular stages, the ndr2 ndr4 ndr5 mutant pollen grains exhibit an abnormal accumulation of callose, precocious germination and burst in anthers, leading to a drastic reduction in fertilization and a reduced seed set. NDR2/4/5 proteins can interact with another group of proteins (MOB1A/1B) homologous to the MOB proteins from the Hippo signaling pathway in yeast and animals. The Arabidopsis mob1a mob1b mutant pollen grains also have a phenotype similar to that of ndr2 ndr4 ndr5 pollen grains. These results provide new evidence demonstrating that the Hippo signaling components are conserved in plants and play important roles in sexual plant reproduction.

BSR and Full-Length Transcriptome Approaches Identified Candidate Genes for High Seed Ratio in Camellia vietnamensis.

(1) Background: C. vietnamensis is very suitable for growth in the low hilly areas of southern subtropical regions. Under appropriate conditions, the oil yield of C. vietnamensis can reach 1125 kg/ha (the existing varieties can reach 750 kg/ha). Moreover, the fruit of C. vietnamensis is large and the pericarp is thick (>5 cm). Therefore, a high seed ratio has become the main target economic trait for the breeding of C. vietnamensis. (2) Methods: A half-sibling population of C. vietnamensis plants with a combination of high and low seed ratios was constructed by crossing a C. vietnamensis female parent. Bulked segregant RNA analysis and full-length transcriptome sequencing were performed to determine the molecular mechanisms underlying a high seed ratio. (3) Results: Seed ratio is a complex quantitative trait with a normal distribution, which is significantly associated with four other traits of fruit (seed weight, seed number, fruit diameter, and pericarp thickness). Two candidate regions related to high seed ratio (HSR) were predicted. One spanned 140.8−148.4 Mb of chromosome 2 and was associated with 97 seed-yield-related candidate genes ranging in length from 278 to 16,628 bp. The other spanned 35.3−37.3 Mb on chromosome 15 and was associated with 38 genes ranging in length from 221 to 16,928 bp. Using the full-length transcript as a template, a total of 115 candidate transcripts were obtained, and 78 transcripts were predicted to be functionally annotated. The DEGs from two set pairs of cDNA sequencing bulks were enriched to cytochrome p450 CYP76F14 (KOG0156; GO:0055114, HSR4, HSR7), the gibberellin phytohormone pathway (GO:0016787, HSR5), the calcium signaling pathway (GO:0005509, HSR6), the polyubiquitin-PPAR signaling pathway (GO:0005515, HSR2, HSR3), and several main transcription factors (bZIP transcription factor, HSR1) in C. vietnamensis.

Genome-Wide Identification and Expression Analysis of the NAC Gene Family in Kandelia obovata, a Typical Mangrove Plant.

The NAC (NAM, ATAF1/2, and CUC2) gene family, one of the largest transcription factor families in plants, acts as positive or negative regulators in plant response and adaption to various environmental stresses, including cold stress. Multiple reports on the functional characterization of NAC genes in Arabidopsis thaliana and other plants are available. However, the function of the NAC genes in the typical woody mangrove (Kandelia obovata) remains poorly understood. Here, a comprehensive analysis of NAC genes in K. obovata was performed with a pluri-disciplinary approach including bioinformatic and molecular analyses. We retrieved a contracted NAC family with 68 genes from the K. obovata genome, which were unevenly distributed in the chromosomes and classified into ten classes. These KoNAC genes were differentially and preferentially expressed in different organs, among which, twelve up-regulated and one down-regulated KoNAC genes were identified. Several stress-related cis-regulatory elements, such as LTR (low-temperature response), STRE (stress response element), ABRE (abscisic acid response element), and WUN (wound-responsive element), were identified in the promoter regions of these 13 KoNAC genes. The expression patterns of five selected KoNAC genes (KoNAC6, KoNAC15, KoNAC20, KoNAC38, and KoNAC51) were confirmed by qRT-PCR under cold treatment. These results strongly implied the putative important roles of KoNAC genes in response to chilling and other stresses. Collectively, our findings provide valuable information for further investigations on the function of KoNAC genes.

Cinnamic acid hybrids as anticancer agents: A mini-review.

Cancer, as a long-lasting and dramatic disease, affects almost one-third of human beings globally. Chemotherapeutics play an important role in cancer treatment, but multidrug resistance and severe adverse effects have already become the main causes of failure in tumor chemotherapy. Therefore, it is an urgent need to develop novel chemotherapeutics. Cinnamic acid contains a ubiquitous α,ß-unsaturated acid moiety presenting potential therapeutic effects in the treatment of cancer as these derivatives could act on cancer cells by diverse mechanisms of action. Accordingly, cinnamic acid derivatives are critical scaffolds in discovering novel anticancer agents. This review provides a comprehensive overview of cinnamic acid hybrids as anticancer agents. The structure-activity relationship, as well as the mechanisms of action, are also discussed, covering articles published from 2012 to 2021.

Benzimidazole hybrids as anticancer drugs: An updated review on anticancer properties, structure-activity relationship, and mechanisms of action (2019-2021).

Cancer, characterized by a deregulation of the cell cycle which mainly results in a progressive loss of cellular differentiation and uncontrolled cellular growth, remains a prominent cause of death across the world. Almost all currently available anticancer agents used in clinical practice have developed multidrug resistance, creating an urgent need to develop novel chemotherapeutics. Benzimidazole derivatives could exert anticancer properties through diverse mechanisms, inclusive of the disruption of microtubule polymerization, the induction of apoptosis, cell cycle (G2/M) arrest, antiangiogenesis, and blockage of glucose transport. Moreover, several benzimidazole-based agents have already been approved for the treatment of cancers. Hence, benzimidazole derivatives are useful scaffolds for the development of novel anticancer agents. In particular, benzimidazole hybrids could exert dual or multiple antiproliferative activities and had the potential to overcome drug resistance, demonstrating the potential of benzimidazole hybrids as potential prototypes for clinical deployment in the control and eradication of cancers. The purpose of the present review article is to provide a comprehensive landscape of benzimidazole hybrids as potential anticancer agents, and the structure-activity relationship as well as mechanisms of action are also discussed to facilitate the further rational design of more effective candidates, covering articles published from 2019 to 2021.

The ritual stance does not apply to magic in general.

Contrary to the author's proposed classification scheme, I argue that most magical practices are better viewed as "instrumental" rather than "ritualistic." Much ethnographic and historical evidence shows that magicians and ritual experts often have elaborate causal theories regarding how magic actions lead to the putative outcome, and the "physical/mechanical" versus "supernatural" distinction in causal mechanisms needs serious reconsideration.

HYAL-1-induced autophagy facilitates pancreatic fistula for patients who underwent pancreaticoduodenectomy.

The main mechanism of hyaluronidase 1(HYAL-1) in the development of postoperative pancreatic fistula (POPF) after pancreatoduodenectomy (PD) was unknown. In this study, a comprehensive inventory of pre-, intra-, and postoperative clinical and biological data of two cohorts (62 pancreatic cancer [PCa] and 111 pancreatic ductal adenocarcinoma [PDAC]) which could induce POPF were retrospectively analyzed. Then, a total of 7644 genes correlated with HYAL-1 was predicted in PDAC tissues and the enriched pathway, kinase targets and biological process of those correlated genes were evaluated. Finally, a mouse pancreatic fistula (PF) model was first built and in vitro studies were performed to investigate the effects of HYAL-1 on PF progression. Our data indicated that preoperative serum HYAL-1 level, pancreatic fibrosis score, and pancreatic duct size were valuable factors for detecting POPF of Grade B and C. The serum HYAL-1 level of 2.07 mg/ml and pancreatic fibrosis score of 2.5 were proposed as the cutoff values for indicating POPF. The bioinformatic analysis and in vitro and in vivo studies demonstrated that HYAL-1 facilitates pancreatic acinar cell autophagy via the dephosphorylation of adenosine 5'-monophosphate-activated protein kinase (AMPK) and signal transducers and activators of transcription 3 (STAT3) signaling pathways, which exacerbate pancreatic secretion and inflammation. In summary, the preoperative serum HYAL-1 was a significant predictor for POPF in patients who underwent PD. Tumor-induced HYAL-1 is one of core risk in accelerating PF and then promoting pancreatic secretion and acute inflammation response through the AMPK and STAT3-induced autophagy.

The deubiquitinase CYLD is a specific checkpoint of the STING antiviral signaling pathway.

Stimulator of interferon genes (STING) is critical for cytosolic DNA-triggered innate immunity. STING is modified by several types of polyubiquitin chains. Here, we report that the deubiquitinase CYLD sustains STING signaling by stabilizing the STING protein. CYLD deficiency promoted the K48-linked polyubiquitination and degradation of STING, attenuating the induction of IRF3-responsive genes after HSV-1 infection or the transfection of DNA ligands. Additionally, CYLD knockout mice were more susceptible to HSV-1 infection than their wild-type (WT) littermates. Mechanistically, STING translocated from the ER to the Golgi upon HSV-1 stimulation; CYLD partially accumulated with STING and interacted selectively with K48-linked polyubiquitin chains on STING, specifically removing the K48-linked polyubiquitin chains from STING and ultimately boosting the innate antiviral response. Our study reveals that CYLD is a novel checkpoint in the cGAS-STING signaling pathway and sheds new light on the dynamic regulation of STING activity by ubiquitination.

Modelling the on-going natural selection of educational attainment in contemporary societies.

There has been substantial increase in education attainment (EA) in both developing and developed countries over the past century. I present a simulation model to examine the potential evolutionary trajectories of EA under current selective pressure in western populations. With the assumption that EA is negatively correlated with fitness and has both a genetic component and a cultural component, I show that when prestige-biased transmission of the EA (i.e. people with more education are more likely to be copied) is present, the phenotype of EA is likely to keep increasing in the short term, yet the genetic component of EA may undergo a constant decline and become the limiting factor in further phenotypic increase.

Diabetic retinopathy predicts cardiovascular mortality in diabetes: a meta-analysis.

BACKGROUND: The prognostic significance of diabetic retinopathy (DR) for cardiovascular diseases (CVD) remained unclear. Therefore, we performed this meta-analysis to assess whether DR predicted CVD mortality in diabetic patients. METHODS: We searched PubMed, Embase, Web of Science and Cochrane Library for cohort studies reporting the association of DR and CVD mortality. Then we pooled the data for analysis. RESULTS: After screening the literature, 10 eligible studies with 11,239 diabetic subjects were finally included in quantitative synthesis. The pooled risk ratio (RR) of DR, mild DR, and severe DR for CVD mortality was 1.83 (95% confidence interval (CI): 1.42, 2.36; p < 0.001), 1.13 (95% CI 0.81, 1.59; p = 0.46), and 2.26 (1.31, 3.91; p = 0.003), respectively, compared to those without DR. In type 2 DM, the patients with DR had a significantly higher CVD mortality (RR: 1.69; 95% CI 1.27, 2.24; p < 0.001). Subgroup analysis also showed a significantly higher CVD mortality in DR according to various regions, study design, data source, and follow-up period (all RR > 1; all P values < 0.05). Data from 2 studies showed no significant correlation of DR and CVD mortality in diabetic patients receiving cardiovascular surgery (RR: 2.40; 95% CI 0.63, 9.18; P = 0.200). CONCLUSIONS: DR is a risk marker of cardiovascular death, and severe DR predicts a doubled mortality of CVD in diabetes. These findings indicate the importance of early identification and management of diabetic patients with DR to reduce the risk of death.

Aromatic Ring Substituted Aaptamine Analogues as Potential Cytotoxic Agents against Extranodal Natural Killer/T-Cell Lymphoma.

A chemical modification study was conducted on the marine natural product aaptamine (1), isolated from the marine sponge Aaptos aaptos. Thirty new derivatives substituted by various aromatic rings at the 3- and 7-positions of aaptamine were prepared by bromination, followed by the Suzuki coupling reaction. Sixteen compounds displayed cytotoxicities to four cancer cell lines (IC50 < 10 µM). In particular, compound 5i demonstrated a significant antiproliferative effect on the extranodal natural killer/T-cell lymphoma (ENKT) cell line SNK-6 with an IC50 value of 0.6 µM. Additionally, compound 5i showed cytotoxicities to multiple lymphoma cell lines, including Ramos, Raji, WSU-DLCL2, and SU-DHL-4 cells.